Expanding Multidrug-Resistant MRSA

We were talking at work the other night about a news report about a new fiercer clone of MRSA. It seems to be adding to it repertoire of resistance. This is of particular interest on my floor as we see a fair share of MRSA infections, they range anywhere from skin-popper with abscesses to post-CABG patients with sternal wound infections. Like Sun Tzu noted, knowledge about your enemy is vital. Here’s some stuff I found.

Panton-Valentine leukocidin

This is what makes the USA300 strain of CA-MRSA so nasty. From the CDC:

Most CA-MRSA strains carry the intracellular toxin Panton-Valentine leukocidin (PVL), which is known for pore formation on polymorphonuclear cells of the host (10,11). In addition, the USA300 clone contains the arginine catabolic mobile element (ACME), which inhibits polymorphonuclear cell production (10)

So in essence it goes after the very cells intended to take it out. The USA300 variant has been most common in skin and soft tissue infections, but now has spread into pneumonia and necrotizing fasciitis. In some places, the USA300 variant is the most predominant form of MRSA, with extremely high mortality rates in pneumonias, especially in the immuno-compromised. In a case study presented at a conference I went to in November, they illustrated a case of PVL positive USA300 MRSA pneumonia. From time of presentation to death in this particular case study was approximately 72 hours. Granted, this was a immuno-compromised individual who had delayed treatment, but the rapid onset, even with supportive therapies was astounding. At the same conference they showed pathology specimens of rat lungs infected with non-USA300 and USA300 MRSA. The non-USA300 lungs looked worse for wear, but the USA300 lungs looked nearly liquid due to the effects of the PVL.

Multi-Drug Resistance

The frightening development in the USA300 variant is the expansion of drug resistance. From a SF Gate.com article:

Further along the gene map are sections that produce resistance to the antibiotics tetracycline, erythromycin, clindamycin, Cipro and mupirocin, a topical ointment often used to kill MRSA colonies living in people’s noses.

And from a MedpageToday.com article:

Thanks to its acquisition of multiple resistance genes, the multi-drug-resistant USA300 strain is also able to battle fluoroquinolones, tetracycline, macrolide, clindamycin, and mupirocin.

This extra level of drug resistance will only increase the use of vancmycin to treat MRSA infections. For many of our MRSA patients, this is all they are on. Increasingly though, we’ve been seeing Levaquin, Cubicin and Zyvox being used to combat the infection, especially in re-offenders (we had one guy come back 3 times with recurrent MRSA sternal infections, even with Wound V.A.C. and I&D therapy the 2nd and 3rd times, he still kept coming back). It’s only a matter of time before we start seeing increased resistance to those drugs. All that we really need s someone with VRE to have a MRSA infection. While there are a few (inter)national cases of vancomycin intermediate resistance Staph and only 1 documented case of resistant Staph, odds are it will only be a matter of time. So instead of MRSA, we’ll be talking bout VRSA. Unfortunately, the hospital becomes a hotbed of evolution due to the co-mingling of conditions and infection. While infection-control tries, they aren’t always able to keep up.

Cross-species evolution

One final reason that USA300 is so nasty is that it appears to have picked up genes from another Staph species. In the SF Gate.com article:

The gene map, published in the British medical journal the Lancet in February 2006, has yielded clues to why this strain spreads so quickly. The bug appears to have swapped genes from Staphylococcus epidermidis, a usually harmless staph species that is commonly found on human skin. Researchers theorize that, by stealing a trick from the milder staph bug, the malevolent USA300 may colonize on human skin more easily than other varieties of MRSA.

This evolution does make it more virulent and a bigger to threat to health-care workers. Think about it. We’re in contact with the patient, doing our nursing duties. Yes, we’re applying the principles of universal precautions and good hand-washing, but still there is a decent chance of us acquiring it. With resistance to mupirocin, knocking out the colonies that may develop on health-care workers becomes infinitely more difficult.

The fascinating element to all of this is the ability of this little bacteria to do this. I didn’t do so great in microbiology and have a basic understanding of resistance, transference and mechanisms of evolution with bacteria and it piques my interest.

Hope you found the information useful . Here’s links to the articles above, it’s good reading.

Picking up on the article Expanding Multidrug Resistance, January 21, 2008 by Wanderer, I wanted to comment a bit more on the environmental sources. Unbeknownst to many, the very park that you may sit upon for a picnic may be a source of antibiotic resistance. The question that also must be ask, is your city really willing to be proactive here?

Here in Santa Barbara, the City uses treated wastewater (reclaimed or recycled water) to irrigate its parks, playing fields, and golf courses. Many cities do this and under the guidance of the State of California’s standards. Unfortunately, those standards don’t work. We tested this reclaimed water from two different cities and those tests showed that it contained multi-antibiotic resistant bacteria. It is not supposed to contain such pathogens and the fact that it does demonstrates a failure of the system to protect the public’s health. Reclaimed water is produced in California under a common set of criteria, thus if one finds it contains drug-resistant bacteria in one location, this is probably universal. As I mentioned, we recently ran tests on another city’s product to test this hypothesis and that water also contained multi-drug resistant bacteria.

In the past while working in the county derm clinics I treated a number of skin infections in young men who were popping drugs. Often these patients are sleeping in the local parks. Many are trading sex with other men for the drugs, thus this adds to the complexity of the situation. There is a fair sized wealthy gay community here where dollars for sex can be converted to drugs or drugs can be exchanged directly.

I am now retired from medicine but am one of the scientists on a Water Environment Research Foundation/ U.S. EPA panel looking at human health risk assessments and antibiotic resistant pathogens arising from treated sewage. Sewer plants, contrary to popular myth, fail to effectively deal with destruction of pathogens. In fact sewer plants multiply antibiotic resistance (see abstracts below from Amy Pruden, et al as well as the one from Sara Firl below). The Water Environment Research Foundation (WERF) is the research arm of the wastewater industry. The WERF/EPA panel on which I sit also includes Drs. Joan Rose and Amy Pruden. Both of these scientists also note deficiencies in current water quality standards. These standards fail to consider either the movement or multiplication of antibiotic resistant bacteria or the transfer of genetic information. This deficiency and ignorance, especially of the public health residual sequelae, leaves a gaping hole in the ability to protect public health. This is especially true for those with compromised immune systems, hence the following.

Last year a series of tests on the reclaimed water used here in Santa Barbara demonstrated that this water contained multi-antibiotic resistant bacteria. This information was given to the city. Before that, in 2003, a WERF study was conducted on whether or not using reclaimed water, as currently produced, was protective of public health. That yearlong study included the City of Santa Barbara’s El Estero sewer plant. The report concluded that the standards against which this water was measured did not protect public health. The report also demonstrated that this water did contain pathogens of public health concern and that the indicator bacteria used by the standards did not adequately measure these pathogens. That report also suggested corrective measures. The City recently informs me that it took no action on that report.

The City is and should be promoting the use of reclaimed water, but as a responsible government, it is also accountable to see that that product does not harm public health. The City has been remiss here. While promoting and profiting from the sale of reclaimed water, it has been less than forthcoming with respect to the current detractors. I appreciate that within a community whose economic engine is retirement and tourism, one does not want to advertise problems, this stance however must carry certain higher ethical standards. The City has repeatedly been informed that its reclaimed water may not be protective of the public health. It appears that the City has and continues to ignore these warnings. This year, the bacterial tests for antibiotic resistance were repeated. Again it was demonstrated that the reclaimed water (called recycled water in statute) contained multi-antibiotic resistant bacteria. The picture has not changed. The City’s response is that the water meets state standards. This is beside the point because the standards have been shown to be failing and the City has the authority to exceed these minimal standards. It apparently refuses to do so, thus leaving its citizens in an awkward position. This stance by the City also places an extra burden on public health resources.

Methicillin resistant Staphylococcus aureus, has broken out of the confines of being a mainly hospital associated pathogen to being a community acquired pathogen (see recent articles on San Francisco gays and MRSA). The reserve of vancomycin as the drug of last resort is now tossed out the window by its current use as a pre-operative prophylactic. The fact that we are finding bacteria that are resistant to vancomycin in the reclaimed water that is liberally used about the city for irrigation raises certain ethical questions for the City. This is especially true since it appears that while having this information for some time, the City has been moribund to effect any correction.

Of interest to be emphasized in tests of the local water, is the fact that amongst the antibiotics against these bacteria are resistant—– is the critical issue that some are resistant is vancomycin. This, until recently was the drug of last resort, held carefully in reserve by CDC’s suggestions. In 2002 or 2003, the levels of background antibiotic resistance were so high that our teaching hospital started using vancomycin as a pre-operative prophylactic. Thus the question that must be ask, but which as yet has not been addressed, is as follows: Does the fact that antibiotic resistant bacteria are found within the reclaimed water used for irrigation of large areas of the city add to the background levels of community acquired resistance? In other words, do we have a revolving door here?

Part of the issue is how to assess the impact? Is there a public health risk? This must be answered. But in doing so, some of the tools formerly used in assessing health impacts are now compromised by the development and transfer of antibiotic resistance. Even using older paradigms on infectious disease such as infective dose, one notes that these no longer function adequately. The ability to transfer genetic information of antibiotic resistant pathogens to the normal gut flora is not considered in these older paradigms. Thus older risk assessments, even if they were done (which they are not) would fail. Through these routes of acquisition and colonization with resistant pathogens, one thus finds that very small numbers, well below the typically classic infective dose will multiply into impressive numbers. A recent report by the American Society of Microbiology (ASM) notes that there are already problems with dose responses because needed data are of limited availability.

Amy Pruden [1] has noted that antibiotic resistant genes (ARGs) translate completely through sewer plants (sewer plants are major mixing chambers for the transfer of genetic information between organisms that otherwise might never come together) into the environment. These same fragments are later picked up in drinking water treatment systems, translate through these systems, their filters, their chlorine treatment—and into the potable water supply. Because these genetic fragments are not “alive”, although being able to transmit pathogenesis to non-pathogens, they are not affected by chlorine levels used in water treatment. Additionally they are so small that they pass through typical filters used in water treatment. This allows them to be found in reclaimed water and thus allows for colonization of the human host. In those with compromised immune systems, this may be even more prevalent and of course more serious.

These bacteria are also able to colonize environmental niches, and animals, besides humans, through ingestion. Thus one’s pet running across a park, if irrigated with reclaimed water, can bring resistance back into the home. However, once ingested, the genetic information may be transferred to normal skin via fecal veneer or within the gut flora, and subsequently to pathogenic bacteria found in humans or animals, making later treatment with particular antibiotics ineffective. Also one must consider transfer of genetic information from these organisms to more robust pathogenic organisms as highlighted by Sjolund et al. (2005) [2] indicating that resistance in the normal flora, which may last up to four-years, might contribute to increased resistance in higher-grade pathogens through interspecies transfer.

Sjolund et al go on to note that since populations of the normal biota are large, this affords the chance for multiple and different resistant variants to develop. This thus enhances the risk for spread to populations of pathogens. Furthermore, there is crossed resistance. For example, vancomycin resistance may be maintained by using macrolides [3].

Walsh (2003) [4] notes that resistance to antibiotics is not a matter of IF but one of WHEN. Schentag, et al. (2003), as reported in Walsh, followed surgical patients with the subsequent results. Pre-op nasal cultures found Staphylococcus aureus 100% antibiotic susceptible. Pre-op prophylactic antibiotics were administered. Following surgery, cephalosporin was administered. Ninety percent of the patients went home at post-op day 2 without infectious complications. Nasal bacteria counts on these patients had dropped from 10/5th to 10/3rd, but were now a mix of sensitive, borderline, and resistant Staphylococcus sp. By comparison, prior to surgery, all of the patients Staphylococcus samples had been susceptible to antibiotics. For the patients remaining in the hospital and who were switched on post-op day 5 to a second generation cephalosporin (ceftazidine), showed bacterial counts up 1000-fold when assayed on post-op day 7 and most of these were methicillin resistant Staphylococcus aureus (MRSA). These patients were switched to a 2-week course of vancomycin. Cultures from those remaining in the hospital on day 21, revealed vancomycin resistant enterococcus (VRE) and candida. Vancomycin resistant enterococci infections can produce mortality rates of between 42 and 81%.

Note in the above, that these patients harbored NO resistant bacteria in their nasal cavities upon entry to the hospital. But what would be the result if there had been inadvertent acquisition of resistance from environmental contamination through sewage byproducts such as reclaimed water? Rusin and Gerba [5] conducted research about the passage from finger to mouth of pathogens found on typical household objects. Drift from sprinkler irrigation is a well-documented process for moving pathogens. Others have documented dust as a mechanical vector for pathogens. Mowing grass is also a mode of dust and drift generation. The ASM report discussed aerosol drift. It is interesting that many homes and offices are adjacent to parks and the issue of drift should thus be of interest.

By definition, an aerosol is able to remain in suspension for prolonged periods because of its low settling velocity. For spherical particles of unit density the settling time for a 3-M fall is noted in the table below. From this, considering the size of both bacteria and viruses, it will be noted that aerosol movement is considerable. Remember that the average bacteria is 1 uM and a virus about 1/00 of that.

TABLE
Assumptions: 5 mph* average wind speed, laminar flow. The assumptions would be upset within an urban setting with buildings, up-currents, and turbulence from traffic.
Particle Diameter………………..Settling Time………..Distance at wind speed 5 mph
100 uM……………………………….10 sec…………………..44 ft
20 uM…………………………………4 minutes……………….1780 feet
10 uM………………………………….17 minutes……………..7480 feet (1.4 miles)
5 uM……………………………………62 minutes……………approx 5 miles
irrigation ditch water > urban/agriculturally impacted river sediments (p < 0.0001), except for sul(II), which was absent in ditch water. It was noted that tet(W) and tet(O) were also present in treated drinking water and recycled wastewater, suggesting that these are potential pathways for the spread of ARGs to and from humans. On the basis of this study, there is a need for environmental scientists and engineers to help address the issue of the spread of ARGs in the environment.

These comments are merely qualifications, not criticisms of Dr. Pruden’s fine paper [1]. Resistance has been attributed to drug over-use. Pruden notes a less well-understood mechanism for the amplification of multi-drug resistance, sewage. The local sewer-treatment plant releases pathogens and resistance to the environment and agriculture[2]. Wastewater treatment intermixes organisms otherwise seldom coming together. Selective pressures increase survival mechanisms [3].

Defense strategies include going dormant, entering the viable but non-culturable (VBNC) state. These VBNC organisms are essentially invisible to laboratory tests used in the wastewater industry. Higgins & Murthy recently reconfirmed this [4] in a paper that raises some serious questions about the efficacy of current standards. Those authors noted that during centrifuged dewatering of sewer sludge, indicators in a VBNC state were resuscitated. The results were several magnitudes greater than standard plate counts had indicated [4]. Such findings raise logical questions. If dewatering by centrifuge brought out the essence of VBNC, would other products of sewage that had not been subjected to the centrifuge also in the VBNC state? If so would they revive in the field following agricultural application of sludge or irrigation with reclaimed wastewater? This seems plausible but needs further study.

Additionally, as stresses increase organisms can acquire genes from or transfer genes to non-related organisms, organisms even within completely different kingdoms [5,6]. There are other materials dumped into the drain that confer resistance. This includes industrial chemicals, heavy metals, and disinfectants. Triclosan a ubiquitous biocide is suspected of inducing resistance, as are many other industrial materials found in sewage [7,8]. Changes to the cellular machinery afford the ability to deal with numerous insults, hence cross-resistance [9].

Many antimicrobials including metabolites enter sewage essentially unchanged to induce resistance in the environment [10]. Kummerer [11,12,13,14,15] and others [16] note levels of antibiotics/pharmaceuticals in sewage able to induce or maintain resistance, hence adding to the risks in crop production through irrigation.

Based on wastewater (sewage) industry and regulatory opinion, the standards, the released effluent, and its use for crop irrigation or the land application of sewage sludge are benign and beneficial activities [17]. If however, one reviews the current medical and scientific literature, a different picture emerges, one that raises serious questions about the benevolence of this activity and efficacy of the underlying standards [18]. Thus, the issue takes on aspects of a political and not a scientific argument [18,19]. In the interim, most regulatory agencies have backed off [20]. This leaves the citizens and patient base essentially standing naked.

In 2002 the NAS/NRC [21] called into question the U.S. EPA Part 503 guidelines for land application of sewage sludge (biosolids) and specifically EPA’s failure to consider antibiotic resistance. As of writing this comment, EPA has shown little if any progress in investigating resistance. A Freedom of Information Act request to EPA on this subject was submitted in February 2005. The agency has not answered that request [20]. Additionally, the agency has not done health hazards risk analyses for pathogens. Notwithstanding these shortcomings, the agency and the wastewater industry continue to promote the use of sewage byproducts in crop production. Salinas Valley is an example.

The Importance of Municipal Sewage Treatment in the Spread of Antibiotic Resistance
106th General Meeting of the American Society for Microbiology
May 21-25, 2006, Orlando, Florida
For more information on any presentation at the 106th General Meeting of the ASM contact Jim Sliwa, ASM Office of Communications at jsliwa@asmusa.org
EMBARGOED UNTIL: Monday, May 22, 9:00 a.m. EDT
(Session 041/Q, Paper Q-032)
Sara Firl
University of Minnesota
Minneapolis, MN, United States
Phone: 612 626 8865firl0002@umn.edu
Our study determined that substantial numbers of antibiotic-resistant bacteria were present in municipal wastewater, and that the existing treatment infrastructure did not adequately prevent release of antibiotic-resistant bacteria into the environment. Many of the bacteria found in the wastewater treatment plant and in the plant effluent were tentatively identified as potential pathogens and were also resistant to multiple antibiotics, raising public health concerns. We believe that wastewater treatment plants could be modified to further prevent the release of resistant bacteria to the environment.
Sara Firl and Leslie Onan performed this study under the supervision of principal investigator Dr. Timothy LaPara at the University of Minnesota, Department of Civil Engineering. Funding was provided by the Center for Urban and Regional Affairs at the University of Minnesota and Geomatrix Consultants, Inc. The work is being presented as a poster at the 106th General Meeting of the American Society for Microbiology in Orlando on May 22.
The spread of antibiotic-resistant bacteria is a major public health concern. Infections previously treatable are increasingly resistant to antibiotics. Scientists believe that the spread of antibiotic resistance results from both misuse of antibiotics and transfer of resistance between bacteria. A potentially large reservoir for antibiotic-resistant bacteria is municipal wastewater. People release resistant bacteria with fecal matter into the wastewater stream, which is collected and treated at municipal treatment facilities before release to the environment. The objective of this study was to investigate how many resistant bacteria were present at municipal wastewater plants and if the existing infrastructure of waste treatment was adequate to remove resistant bacteria before discharge.
In our study, the effect of effluent treatment (clarification and disinfection) and biosolids treatment (sludge digestion) on the removal of antibiotic-resistant bacteria was investigated at three wastewater treatment facilities. We found substantial numbers of resistant bacteria at the wastewater treatment facilities and that, although effluent treatment reduced the numbers of bacteria, large quantities of resistant bacteria were discharged. Numerous bacteria isolated from the effluent stream were resistant to multiple antibiotics and closely related to potentially pathogenic bacteria. Our research suggests that the existing wastewater treatment infrastructure should be modified to better prevent release of these potentially dangerous bacteria to the environment.

45+/- yrs of felony altering of sewer and water lines was discovered here in Fresno, CA. Leaving a trail of respiratory/lung, asthma, illness, infections, amputation, death. Upon catching the group in action, I reported it to the City of Fresno who then threatened me and committed perjury in order to DISCREDIT their own records, which verify exactly what has been taking place. Massive cover up at the cost of human lives.
Naturally, they deny that any of this has taken place, despite the evidence from one end of town to the other. No one oversees this dept. which is tragic. Residents are being wiped out.

It is good to see medical people involved in research. However, MRSA is just the tip of this iceberg. Please see a new draft article on the necrotizing infections you can expect to see now and in the future at http://thewatchers.us/H2S_bacteria_odor.html

Who is?

Wanderer WAS a Charge Nurse on a busy telemetry unit somewhere in metro Portland. He reads, he writes, he cooks and is a passionate bicycle commuter. Any patient account has been scrubbed to best of his ability. As the saying goes, if you think it's about you, it ain't.